Postoperative beneficial effects of esmolol in treated hypertensive patients undergoing laparoscopic cholecystectomy

Abstract

Background

In an attempt to decrease haemodynamic instability and early postoperative complications such as nausea, vomiting, and pain, esmolol was added to the routine alfentanil infusion of patients with treated hypertension undergoing laparoscopic cholecystectomy.

Methods

Forty consecutive ASA class II patients with controlled hypertension about to undergo laparoscopic cholecystectomy were randomized into two groups: an esmolol group (Group E, n=20) was given a 1 mg kg⁻¹ bolus of esmolol and a placebo group (Group P, n=20) was given an identical volume of Ringer’s lactate. The rate of esmolol infusion was adjusted to keep the heart rate between 65 and 75 beats min⁻¹ and was 5–10 µg kg⁻¹ min⁻¹ throughout the procedure. After operation, patients reported their nausea using a four-point scale.

Results

Esmolol had an opioid-sparing effect intraoperatively (P=0.001). Postoperative requirements for antiemetics were significantly less in the esmolol group, with no antiemetics given to eight patients. In the placebo group, however, all patients required at least one dose of antiemetic (P=0.007). The frequency of PONV did not correlate to the amounts of alfentanil, propofol, postoperative antiemetics consumed, or to female gender, non-smoking status, and history of PONV or motion sickness. Postoperative analgesic consumption in Group E was significantly lower than in Group P (P=0.012).

Conclusions

Esmolol had an opioid-sparing effect in the intraoperative and immediate postoperative period in hypertensive patients undergoing laparoscopy. When combined with alfentanil, it was more effective than placebo in decreasing early PONV.

Postoperative nausea and vomiting (PONV) are unpleasant side-effects of laparoscopy. They occur in 40–75% of patients and can significantly delay hospital discharge. Female gender, non-smoking status, a history of PONV or motion sickness, postoperative use of opioids, and preoperative and orthostatic hypotension are major risk factors for the development of PONV.^1–3 ASA II patients with treated hypertension are at increased risk of early postoperative hypotension, PONV, and longer postoperative stay.⁴ Maintaining a stable intraoperative blood pressure has been found to be an effective method of preventing PONV.⁵

Esmolol, an ultra short-acting cardio-selective ß₁-receptor antagonist, has been shown to blunt haemodynamic responses to perioperative noxious stimuli.^6–9 In this study, we investigated the effect of a perioperative esmolol infusion on postoperative pain and nausea and vomiting in patients with treated hypertension undergoing laparoscopic cholecystectomy.

Methods

After obtaining approval from the ethics committee of our hospital, 40 consecutive ASA class II patients with treated hypertension (as defined by the European Society of Cardiology)¹⁰ who were to undergo elective laparoscopic cholecystectomy gave informed consent and were included in the study. Patients on regular antihypertensive medication whose arterial blood pressure was ≤140/90 during the preoperative anaesthetic visit 1–3 days before surgery were approached about entering the study. Smoking status and any history of motion sickness or previous PONV were recorded. Exclusion criteria were: current treatment with a ß-blocker or calcium channel blocker, chronic use of opioid analgesics, history of asthma or reactive airway disease, diabetes mellitus, allergy to any of the medications used in the study, obesity, or cachexia beyond the ideal body weight by at least 50%, severe haemorrhage during operation or conversion to open cholecystectomy. All patients were taking an angiotensin-converting enzyme inhibitor, with or without a diuretic as antihypertensive therapy. The angiotensin-converting enzyme inhibitor was stopped only on the morning of the operation.¹¹ An anaesthetist not involved in the care of the patient prepared the esmolol and placebo solutions and held the randomization codes until the end of the study. Both the patients and the anaesthetist in charge were blinded to group allocation for the duration of the study. An anaesthetist not involved in any way with postoperative patient evaluation, and who had no prior patient contact, conducted the entire course of anaesthesia.

All patients were premedicated with 2 mg of i.v. midazolam and received 10 ml kg⁻¹ of Ringer’s lactate solution before their transfer to the operating room. Patients were randomized into two groups: the esmolol group (Group E, n=20) and placebo group (Group P, n=20). Group E patients received 1 mg kg⁻¹ of esmolol i.v. immediately before induction, whereas Group P patients received a placebo infusion of the same volume of Ringer’s lactate solution infused more than 3 min. After induction, an i.v. infusion of esmolol at a rate of 5–10 µg kg⁻¹ min⁻¹ was continued to maintain the heart rate between 65 and 75 beats min⁻¹. Group P patients received an equivalent volume of Ringer’s lactate solution. Both infusions were terminated immediately after extubation.

Before surgery all patients received 75 mg of diclofenac i.m., 10 mg of metoclopramide HCl i.v., and 4 mg of dexamethasone i.v. Anaesthesia was induced with 10 µg kg⁻¹ of alfentanil and propofol which was titrated to loss of the eyelash reflex. Cis-atracurium was given and patients were intubated. Controlled ventilation was performed with an Aestiva 3000^® (Datex-Ohmeda, Madison, WI, USA) ventilator and end-tidal CO₂ was kept between 3.9 and 4.6 kPa during the procedure. Maintenance of anaesthesia was with an alfentanil infusion and desflurane at an inspired concentration of 2.5% in an inhaled mixture of 65% nitrous oxide and oxygen. The inspired desflurane concentration was adjusted to maintain a target BIS value of 60 during the operation. Supplemental neuromuscular block was provided with cis-atracurium. The alfentanil infusion was continued at a rate of 0.5–3.0 µg kg⁻¹ min⁻¹ in order to keep the mean arterial blood pressure (MABP) within 20% of the value that was recorded before the administration of premedication, and was terminated after excision and extraction of the gallbladder. Desflurane and nitrous oxide were discontinued when the laparoscope was withdrawn and the effects of neuromuscular blocking agents were reversed at the end of the procedure. Body core temperature was measured with an oesophageal temperature probe and maintained at 36°C. Intraperitoneal pressure was kept between 12 and 14 mm Hg during insufflations of carbon dioxide. The total doses of propofol, esmolol, and alfentanil given to each patient were calculated and recorded. Haemodynamic instability was defined as heart rate <60 beats min⁻¹ or a MABP <75 mm Hg.

PONV were graded on a four-point scale: 1, no nausea; 2, mild nausea; 3, severe nausea; and 4, retching or vomiting. Patients with PONV received 10 mg of metoclopramide HCl i.v. The total dose of antiemetics was calculated during the first 24 h after operation. Observers were blinded with respect to treatment groups.

A mixture of 5 ml each of lidocaine 1% and bupivicaine 0.25% was injected around the muscular fascia and both sides of the skin incision at the end of the operation. Tramadol hydrochloride (100 mg, up to a maximum of 400 mg), mixed in 100 ml normal saline, was given as an i.v. infusion more than 15 min together with 75 mg of diclofenac sodium (maximum of 150 mg) i.m. for postoperative pain control if the VAS was more than 3. The total dose of analgesics used during the first 24 h after operation was calculated.

Statistical analysis

All values are reported as mean (sd) or 95% CI. Differences between the groups were analysed using either Student's t-test or repeated measures of anova for continuous variables, and two-sided Fisher’s exact tests for categorical variables. The Mann–Whitney U-test was used to compare non-parametric values. Spearman’s rank order correlation was used to assess correlation between the variables. Statistica for Windows® v5.1 (StatSoft Inc., USA) software package was utilized for statistical analysis and a P-value of <0.05 was considered statistically significant.

Results

The characteristics of the patients and durations of anaesthesia and the laparoscopy were similar in both groups (Table 1). Patients had no electrolyte abnormalities. The mean heart rate did not decrease below 60 beats min⁻¹ in any patient, and was not significantly different between the esmolol and the placebo groups at any point before, during, or after the procedure. In addition, the MABP did not decrease below 75 mm Hg in any patient in either group, and at no point during the procedure was the MABP of the Groups P and E patients significantly different. In Group E, the mean (sd) total dose of esmolol was 115.1 (0.5) mg. The total dose of intraoperative alfentanil was significantly less in Group E (P=0.001).

Although all patients in Group P required antiemetics at least once, eight patients in Group E did not need them at all (P=0.003) (Table 2). PONV was less severe in the esmolol group (P<0.001), and was not related to the amounts of alfentanil or propofol consumed; nor to female gender, smoking status, history of PONV, or motion sickness (Table 3).

When the number of doses of postoperative analgesics (diclofenac or tramadol) were compared, Group E patients required none in 35%, and one in 60% of patients. In Group P, 70% of patients required one and 30% required two or more doses of postoperative analgesic (P=0.0032, Fisher’s exact test). No patient recalled any of the operative events.

Discussion

ASA II patients with treated hypertension are at increased risk of early postoperative hypotension, PONV, and longer postoperative hospital stays.⁴ There are data to suggest that maintaining perioperative blood pressure stability is an effective means of preventing PONV.⁵ Coloma and colleagues⁸ found that esmolol decreased the incidence of PONV more than remifentanil after desflurane-based fast-track anaesthesia for outpatient gynaecologic laparoscopic surgery. However, Smith and colleagues¹² found that esmolol, when compared with alfentanil as a supplement to propofol–nitrous oxide anaesthesia, did not decrease the incidence of PONV in outpatients undergoing arthroscopic procedures.

Several risk factors for PONV have been identified, including intraoperative haemodynamic instability, hypovolaemia, gender, orthostatic hypotension, and motion sickness.^1–3,5,13 ß-blocking agents, such as esmolol, with or without opioid analgesics, are useful to prevent haemodynamic changes during the perioperative period.^6–9,14 Haemodynamic instability did not occur in any of our patients, and HR and MABP were not significantly different in the two groups during the procedure.

Potential confounding factors are similarly distributed between the two groups in this study. To prevent hypovolaemia from precipitating PONV, all patients were given a preoperative bolus of lactated Ringer’s solution.¹³ The gender mix of our patients was the same in both groups. The incidence of motion sickness was not significantly different between Groups E and P. In summary, esmolol significantly decreased the postoperative antiemetic requirement in our patients.

We used a low dose of esmolol [mean (sd) 10.1 (2.9) μg kg⁻¹ min⁻¹] and intraoperative sympathetic responses were not significantly different from the placebo group, as attested by similar heart rate and blood pressure responses. However, we did find that the total dose of alfentanil used was lower in Group E. Koivusalo and colleagues⁷ found that high-dose esmolol (200 µg kg⁻¹ min⁻¹) with alfentanil effectively blunted the sympathetic response to the painful stimulus of pneumoperitoneum in ASA I and II patients, whereas alfentanil alone was ineffective. The difference in esmolol dose needed to effectively blunt sympathetic responses to intraoperative manipulation may be due to different sensitivity to ß-blockers between ethnic groups with hypertension in these studies.¹⁵

Esmolol was found to possess analgesic-like properties in a rodent model by Davidson and colleagues.¹⁶ As in our study, two previous studies found that a continuous intraoperative infusion of esmolol decreased the use of postoperative analgesics.^6,17 In another study, intraoperative esmolol did not change the need for analgesics during the postoperative period.⁷ However, the mechanisms responsible for the analgesic-like effects of esmolol are yet to be clarified.

Limitations of our study include a small patient population. These beneficial results should be sought in studies with larger groups of patients.

Patients with treated hypertension have been reported to be at greater risk of PONV. Our study suggests that, in the setting of laproscopic surgery, esmolol maintains haemodynamic stability, decreases PONV and reduces alfentanil requirements for intraoperative analgesia, and tramadol requirements for postoperative analgesia.

Acknowledgement

We would like to thank to Dr Guven Olgac, FETCS, for his assistance with preparation of this manuscript.

References